Insecticidal Substituted Biphenylmethyl Oxime Ethers - ACS Publications

Chapter 16 Insecticidal Substituted Biphenylmethyl Oxime Ethers

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on June 11, 2015 | http://pubs.acs.org Publication Date: November 3, 1987 | doi: 10.1021/bk-1987-0355.ch016

Thomas G. Cullen, Charles J. Manly, Philip A. Cruickshank, and Sandra M. Kellar Agricultural Chemical Group, FMC Corporation, P.O. Box 8, Princeton, NJ 08543 Replacement of the normal pyrethroid ester by alternative linkages usually leads to diminution of biological activity. One important exception to this general phenomena is several oxime ether derivatives, in particular, 3-phenoxybenzyl derivatives of various alkyl aryl ketones. Pyrethroid esters derived from certain 2-substituted-[1,1'-biphenyl]-3-methanols have been shown to possess initial and residual activity surpassing that of esters derived from 3-phenoxybenzyl alcohol. Now it has been demonstrated that the same enhancement of activity was observed for alkyl aryl oxime ethers of certain [1,1'-biphenyl]-3-methanols compared to the corresponding 3-phenoxybenzyl alcohol derived oximes. The synthesis, biological activity, including soil activity, structure-activity relationships and toxicity of several of these biphenylmethyl oxime ethers are described. Many s y n t h e t i c p y r e t h r o i d s w i t h e x c e l l e n t i n s e c t i c i d a l a c t i v i t y have been d i s c o v e r e d t h r o u g h m o d i f i c a t i o n o f t h e a c i d and a l c o h o l m o i e t i e s o f t h e n a t u r a l p y r e t h r i n s . However, r e p l a c e m e n t o f t h e p y r e t h r o i d e s t e r l i n k a g e w i t h an a l t e r n a t i v e l i n k a g e u s u a l l y l e a d s t o compounds o f d i m i n i s h e d b i o l o g i c a l a c t i v i t y ( i ) . One e x c e p t i o n t o t h i s t r e n d o f lower a c t i v i t y i s t h e c l a s s o f compounds w h e r e i n the oxime l i n k a g e i s i n t r o d u c e d i n p l a c e o f the e s t e r l i n k a g e i n the f e n v a l e r a t e s e r i e s . A d d i t i o n a l l y , o n l y t h e E-isomer o f t h e a l k y l a r y l oxime e t h e r s i s r e p o r t e d t o be i n s e c t i c i d a l ( 2 ^ 4 ) . P y r e t h r o i d e s t e r s d e r i v e d from [ 1 , 1 ' - b i p h e n y l ] - 3 - m e t h a n o l have been o f i n t e r e s t a t FMC(5^7). I t has been r e p o r t e d t h a t [1,1'biphenyl]-3-methanol e s t e r i f i e d with both cis-3-(2-chloro-3,3,3t r i f l u o r o - l - p r o p e n y l ) - 2 , 2 - d i m e t h y l c y c l o p r o p a n e c a r b o x y l i c a c i d and ç_is - 3 - (2 , 2 - d i c h l o r o e t h e n y l ) - 2 , 2 - d i m e t h y l c y c l o p r o p a n e c a r b o x y l i c acid p r o d u c e d e s t e r s w h i c h have i n i t i a l and r e s i d u a l a c t i v i t y s u r p a s s i n g t h a t o f p e r m e t h r i n a g a i n s t a number o f i n s e c t s . I t o c c u r r e d t o u s t h a t t h i s same enhancement o f a c t i v i t y might be o b s e r v e d w i t h a l k y l

0097-6156/87/0355-0173S06.00/0 © 1987 American Chemical Society

In Synthesis and Chemistry of Agrochemicals; Baker, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS

a r y l methanone oxime e t h e r s o f 2 - s u b s t i t u t e d - [ 1 , 1 - b i p h e n y l ] - 3 methanols compared t o those a l k y l a r y l methanone oxime e t h e r s d e r i v e d from 3-phenoxybenzyl a l c o h o l . We w i s h t o r e p o r t on the s y n t h e s i s , b i o l o g i c a l a c t i v i t y , mammalian t o x i c o l o g y , and s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s o f a l k y l a r y l methanone oxime e t h e r s d e r i v e d from 2 - m e t h y l [ 1 , 1 ' - b i p h e n y l ] - 3 - m e t h a n o l .


MATERIALS AND

METHODS

N u c l e a r magnetic resonance (^-H NMR) s p e c t r a were r e c o r d e d on e i t h e r a V a r i a n Τ-60 o r a V a r i a n FT-80A w i t h Me4Si as an i n t e r n a l standard. I n f r a r e d s p e c t r a were o b t a i n e d on a P e r k i n - E l m e r 735B i n f r a r e d s p e c t r o p h o t o m e t e r . A l l b o i l i n g p o i n t s and m e l t i n g p o i n t s are u n c o r r e c t e d . T h i n l a y e r chromatography (TLC) u t i l i z e d s i l i c a g e l 60 F-254 c h r o m a t o p l a t e s (0.2-5 mm t h i c k n e s s ) . Chemicals ( 4 - C h l o r o p h e n y l ) c y c l o p r o p y l Ketone. Under a d r y n i t r o g e n atmosphere, a m i x t u r e o f 1.6 g (0.066 mole) o f magnesium, 7.9 g (0.066 mole) o f c y c l o p r o p y l bromide, 20 mL o f anhydrous d i e t h y l e t h e r and 60 mL o f anhydrous t e t r a h y d r o f u r a n was h e a t e d a t r e f l u x f o r 2.5 h o u r s . The s t i r r e d m i x t u r e was c o o l e d t o room temperature and a s o l u t i o n o f 9.04 g (0.066 mole) o f 4 - c h l o r o b e n z o n i t r i l e i n 40 mL o f anhydrous t e t r a h y d r o f u r a n was added o v e r one hour. A f t e r complete a d d i t i o n , the m i x t u r e was h e a t e d a t r e f l u x f o r two h o u r s , t h e n c o o l e d t o room t e m p e r a t u r e . A 100 mL p o r t i o n o f 2N h y d r o c h l o r i c a c i d was added s l o w l y t o the m i x t u r e and s t i r r e d f o r one h o u r . The m i x t u r e was e x t r a c t e d w i t h t h r e e 100 mL p o r t i o n s o f d i e t h y l e t h e r . The combined e x t r a c t s were washed w i t h one 25 mL p o r t i o n o f w a t e r , d r i e d o v e r anhydrous magnesium s u l f a t e and filtered. The f i l t r a t e was c o n c e n t r a t e d under r e d u c e d p r e s s u r e t o g i v e an o i l w h i c h was d i s t i l l e d t o g i v e 3.9 g o f p r o d u c t . The ^-H NMR was c o n s i s t e n t w i t h the p r o p o s e d s t r u c t u r e . (Ε.Z)-(4-Chlorophenyl)cyclopropyl Methanone Oxime. A m i x t u r e o f 25.0 g (0.138 mole) o f ( 4 - c h l o r o p h e n y l ) ( c y c l o p r o p y l ) k e t o n e , 15.0 g (0.216 mole) o f h y d r o x y l a m i n e h y d r o c h l o r i d e , 27.6 g (0.69 mole) o f sodium h y d r o x i d e , 50 mL o f 95% e t h a n o l and 7 mL o f w a t e r was r e f l u x e d f o r t e n m i n u t e s . A f t e r c o o l i n g , the c o n t e n t s were p o u r e d i n t o a s o l u t i o n o f 500 mL o f 1.6 Ν h y d r o c h l o r i c a c i d . The r e s u l t i n g o i l was e x t r a c t e d w i t h t h r e e 100 mL p o r t i o n s o f d i e t h y l e t h e r . The combined e x t r a c t s were washed w i t h one 50 mL p o r t i o n o f w a t e r , d r i e d o v e r anhydrous magnesium s u l f a t e and f i l t e r e d . The f i l t r a t e was c o n c e n t r a t e d under reduced p r e s s u r e t o g i v e 11.7 g o f Ε,Ζ-oxime. The ^-H nmr was c o n s i s t e n t w i t h the p r o p o s e d s t r u c t u r e . ( E ) - ( 4 - C h l o r o p h e n y l ) ( c y c l o p r o p y l ) Methanone Oxime. A s o l u t i o n o f 25.42 g (0.13 mole) o f (Ε,Z)-(4-chlorophenyl)(cyclopropyl)methanone oxime i n 100 mL o f anhydrous d i e t h y l e t h e r was t r e a t e d w i t h anhydrous hydrogen c h l o r i d e . The r e s u l t a n t p r e c i p i t a t e was f i l t e r e d and washed w i t h t h r e e 50 mL p o r t i o n s o f anhydrous d i e t h y l e t h e r . The p r e c i p i t a t e was c o l l e c t e d and added t o 500 mL o f an aqueous 10% sodium c a r b o n a t e s o l u t i o n t o y i e l d 23.5 g o f E-oxime. The 1H NMR was c o n s i s t e n t w i t h the p r o p o s e d s t r u c t u r e .



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175

(E)-(4-Chlorophenyl)(cyclopropyl)methanone 0-Γ2-Methylf1.1'biphenyl]-3-vl)methvnoxime. To a s o l u t i o n o f 0.23 g ( 0 . 0 1 mole) o f sodium e t h o x i d e i n 1 0 mL o f e t h a n o l was added 1.96 ( 0 . 0 1 mole) o f ( E ) - ( 4 - c h l o r o p h e n y l ) ( c y c l o p r o p y l ) m e t h a n o n e oxime. After s t i r r i n g a t room temperature f o r one hour, the m i x t u r e was evap o r a t e d to d r y n e s s . The r e s i d u e was d i s s o l v e d i n a minimum amount o f s o l v e n t c o n s i s t i n g o f Ν,Ν-dimethylformamide and t - b u t a n o l ( 9 : 1 r a t i o ) and t r e a t e d w i t h 2.16 g ( 0 . 0 1 mole) o f 3 - c h l o r o m e t h y l - 2 methyl[1,1'-biphenyl]. The m i x t u r e was s t i r r e d o v e r n i g h t a t room temperature and t h e n p o u r e d i n t o 50 mL o f water. The r e s u l t i n g o i l was e x t r a c t e d w i t h t h r e e 50 mL p o r t i o n s o f t o l u e n e . The combined o r g a n i c l a y e r s were washed w i t h one 1 0 mL p o r t i o n o f aqueous 1 0 % sodium h y d r o x i d e , one 1 0 mL p o r t i o n o f water and d r i e d over anhy drous magnesium s u l f a t e . The f i l t r a t e was c o n c e n t r a t e d under r e d u c e d p r e s s u r e and the r e s i d u e was p u r i f i e d by column chroma t o g r a p h y on s i l i c a g e l , e l u t i n g w i t h t o l u e n e to g i v e 0.83 g o f Eoxime e t h e r as an o i l ; ^-H NMR ( C D C 1 ) δ 0.5-0.95 (m,5H), 2.10 ( s , 3 H ) ; 5.25 ( s , 2 H ) ; 7.08-7.42 (m,12H). 3

B i o l o g i c a l Methods The compounds were e v a l u a t e d f o r i n s e c t i c i d a l and a c a r i c i d a l a c t i v i t y a g a i n s t the f o l l o w i n g s p e c i e s : cabbage l o o p e r ( T r i c h o p l u s i a n i [Hubner]), M e x i c a n bean b e e t l e ( E p i l a c h n a v a r i v e s t i s Muls), s o u t h e r n armyworm (Spodoptera e r i d a n i a [Cram]), pea a p h i d ( A c v r t h o s i p h o n pisum [ H a r r i s ] ) , t w o s p o t t e d s p i d e r m i t e ( T e t r a n y c h u s u r t i c a e [Koch]) and s o u t h e r n c o r n rootworm ( D i a b r o t i c a undecimpunctata Howardi). The a c t i v i t y a g a i n s t M e x i c a n bean b e e t l e (MBB), s o u t h e r n armyworm (SAW) and cabbage l o o p e r (CL) was d e t e r m i n e d by s p r a y i n g the upper and lower s u r f a c e s o f the l e a v e s o f p i n t o bean p l a n t s w i t h t e s t s o l u t i o n u n t i l r u n - o f f and i n f e s t i n g w i t h t h i r d i n s t a r l a r v a e ( t e n l a r v a e f o r each o f two r e p l i c a t e s f o r each compound) a f t e r the f o l i a g e had d r i e d . The a c t i v i t y a g a i n s t pea a p h i d (PA) was d e t e r m i n e d i n s i m i l a r f a s h i o n , e x c e p t t h a t b r o a d bean p l a n t s were u s e d and the l e a v e s were i n f e s t e d w i t h a d u l t a p h i d s . The a c t i v i t y a g a i n s t m i t e s (TSM) was d e t e r m i n e d on p i n t o bean plants. The bean l e a v e s were i n f e s t e d w i t h a d u l t m i t e s (about 75 m i t e s f o r each o f two r e p l i c a t e s f o r each compound), t h e n s p r a y e d u n t i l the r u n - o f f w i t h t e s t s o l u t i o n . The p i n t o bean p l a n t s were i n f e s t e d by p l a c i n g s e c t i o n s o f p l a n t s from e a r l i e r i n f e s t e d p l a n t s onto the l e a v e s o f the t e s t p l a n t s . To p r e v e n t escape o f the i n s e c t s from the t e s t s i t e , the t e s t p l a n t o r the i n c i s e d l e a v e s were p l a c e d i n capped p a p e r cups o r o t h e r a p p r o p r i a t e c o n t a i n e r s . The t e s t s were t r a n s f e r r e d t o a h o l d i n g room a t 25°C and 50% r e l a t i v e h u m i d i t y f o r an exposure p e r i o d o f 48 h o u r s . A t the end o f t h i s time the dead and l i v i n g i n s e c t s / m i t e s were c o u n t e d and the p e r c e n t m o r t a l i t y was calculated. The r e l a t i v e p o t e n c y o f each compound was c a l c u l a t e d as the r a t i o o f the L D 5 0 o f c y p e r m e t h r i n ( i n c l u d e d i n a l l t e s t s as the s t a n d a r d ) to t h a t o f the e x p e r i m e n t a l compound.



176


The a c t i v i t y a g a i n s t t h e s o u t h e r n c o r n rootworm (SCR) was d e t e r m i n e d i n a s o i l environment a t t e s t i n g r a t e s o f 10, 4, 2 and 0.5 ppm i n s o i l and f o r r e s i d u a l p e r i o d s o f 7, 14 and 28 days. For a t e s t i n g r a t e o f 10 ppm, 15 mg o f t e s t compound was d i s s o l v e d i n 100 ml o f an a c e t o n e - w a t e r - s u r f a c t a n t stock s o l u t i o n (1:9 a c e t o n e - w a t e r , one drop o f o c t y l p h e n o x y p o l y e t h o x y e t h a n o l s u r f a c t a n t f o r each 100 ml o f a c e t o n e - w a t e r ) t o g i v e a s t o c k s o l u t i o n c o n t a i n i n g 150 ppm o f t e s t compound, and 2 ml o f t h e 150 ppm s t o c k s o l u t i o n was t h o r o u g h l y mixed w i t h 30 ml o f a i r - d r i e d t o p s o i l i n a 120 mL p l a s t i c cup t o g i v e a c o n c e n t r a t i o n o f t e s t compound i n t h e s o i l o f 10 ppm. F o r a t e s t i n g r a t e o f 4 ppm, 2 mL o f a 60 ppm s t o c k s o l u t i o n o f t e s t compound i n acetone-waters u r f a c t a n t was admixed w i t h 30 mL o f a i r - d r i e d t o p s o i l i n a p l a s t i c cup. S i m i l a r l y , 2 mL o f a 30 ppm t e s t compound s t o c k s o l u t i o n mixed w i t h 30 mL o f a i r - d r i e d s o i l gave a t e s t i n g r a t e o f 2 ppm, and 2 mL o f a 7.5 ppm t e s t compound s t o c k s o l u t i o n mixed w i t h 30 mL o f d r y t o p s o i l gave a t e s t i n g r a t e o f 0.5 ppm. Each cup o f t r e a t e d t o p s o i l was capped w i t h a p l a s t i c l i d and s t o r e d f o r 7, 14, and 28 days. On t h e t e r m i n a l day o f t h e s t o r a g e p e r i o d , t h e cups were i n f e s t e d w i t h s o u t h e r n c o r n rootworm l a r v a e (10 specimens f o r each o f t h e two r e p l i c a t e s f o r each compound), and a k e r n e l o f g e r m i n a t i n g c o r n was added t o each cup as a f o o d supply. The cups were recapped and r e t u r n e d t o s t o r a g e f o r t h r e e days. A t t h e end o f t h i s time t h e dead and l i v i n g rootworms were c o u n t e d and t h e p e r c e n t m o r t a l i t y was c a l c u l a t e d . RESULTS AND DISCUSSION C h e m i s t r y . The m a j o r i t y o f t h e a l k y l a r y l methanone oxime e t h e r s were s y n t h e s i z e d as shown i n F i g u r e 1. The a l k y l a r y l methanones were p r e p a r e d by e i t h e r o f two methods. I n t h e f i r s t method, t h e a p p r o p r i a t e l y - s u b s t i t u t e d b e n z o n i t r i l e was t r e a t e d w i t h the d e s i r e d a l k y l m a g n e s i u m h a l i d e t o g i v e t h e d e s i r e d k e t o n e ( 8 ) . The second approach i n v o l v e d t h e a p p r o p r i a t e l y s u b s t i t u t e d b e n z o i c a c i d and c o n v e r s i o n t o t h e a c i d c h l o r i d e . S u b s e q u e n t l y , t h e a c i d c h l o r i d e i s t r e a t e d w i t h 0,Ν-dimethylhydroxylamine h y d r o c h l o r i d e ( 2 ) . T h i s methoxymethylbenzamide i s t r e a t e d w i t h an a l k y l magnesium h a l i d e t o g i v e t h e a l k y l a r y l methanone. These k e t o n e s were p u r i f i e d by d i s t i l l a t i o n . The k e t o n e s were c o n v e r t e d t o t h e E , Z - a l k y l a r y l methanone oximes by a v a r i e t y o f methods. Most commonly, t h e k e t o n e and h y d r o x y l a m i n e h y d r o c h l o r i d e were suspended i n e t h a n o l and two e q u i v a l e n t s o f p y r i d i n e added. A f t e r i s o l a t i o n , t h e oximes were t r e a t e d w i t h anhydrous hydrogen c h l o r i d e gas t o g i v e t h e hydrogen c h l o r i d e s a l t o f t h e E - a l k y l a r y l methanone o x i m e ( 1 0 ) . The r e s u l t i n g s a l t was t r e a t e d w i t h d i l u t e sodium b i c a r b o n a t e t o y i e l d the d e s i r e d E - a l k y l a r y l methanone oxime. E a r l i e r l i t e r a t u r e r e p o r t s i n d i c a t e d t h a t E-aldoxime was c o n v e r t e d t o t h e Z-aldoxime under s i m i l a r c o n d i t i o n s ( 1 1 ) . The a l k y l a r y l methanone oximes c a n be c o n v e r t e d t o oxime e t h e r s b y s e v e r a l methods. The u s u a l a l k y l a t i o n p r o c e d u r e u t i l i z e d was a phase t r a n s f e r c a t a l y z e d a l k y l a t i o n w h e r e i n t h e E - a l k y l a r y l


16.

CULLENETAL.



R

χ R

X R « alkyl, cycloalkyl R = [l,r-biphenyl]-2-methyl-3-yl R" 3-phenoxybenzyl 1

s

F i g u r e 1.

Synthesis

o f A l k y l A r y l Methanone Oxime E t h e r s


178



oxime, 3 - c h l o r o m e t h y l - 2 - m e t h y l - [ 1 , 1 ' - b i p h e n y l ] , powdered p o t a s s i u m h y d r o x i d e and tetrabutylammonium bromide were r e f l u x e d i n t e t r a hydrofuran. A f t e r work-up, the E - a l k y l a r y l methanone oxime e t h e r was p u r i f i e d by column chromatography(12). T a b l e I l i s t s the a l k y l a r y l methanone oxime e t h e r s p r e p a r e d i n t h i s s t u d y . B i o l o g y . The a l c o h o l p o r t i o n o f most p y r e t h r o i d s c o n t a i n s two c e n t e r s o f u n s a t u r a t i o n s e p a r a t e d by a b r i d g i n g atom. I n a l l e t h r i n and r e s m e t h r i n t h i s s t r u c t u r a l f e a t u r e i s r e p r e s e n t e d by the c a r b o n atom o f the methylene groups, w h i l e i n p e r m e t h r i n , the b r i d g i n g group i s oxygen. Q u a l i t a t i v e d i s c u s s i o n s o f s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s o f p y r e t h r o i d s have g e n e r a l l y p o i n t e d t o t h i s f e a t u r e as a r e q u i r e m e n t f o r i n s e c t i c i d a l a c t i v i t y . More r e c e n t l y i t had been s u g g e s t e d t h a t the l a c k o f c o p l a n a r i t y between the c e n t e r s o f u n s a t u r a t i o n , t h a t r e s u l t s from the p r e s e n c e o f the b r i d g i n g group, p r o v i d e s optimum f i t a t the a c t i v e s i t e . A s e r i e s o f monosubstit u t e d b e n z y l a l c o h o l s p r e p a r e d a t FMC r e v e a l e d t h a t i n s e c t i c i d a l a c t i v i t y can be o b t a i n e d when the s u b s t i t u e n t has two c e n t e r s o f u n s a t u r a t i o n even i f i t l a c k s an atom b r i d g i n g those c e n t e r s (5.). I n t h i s work i t was r e p o r t e d t h a t the b i o l o g i c a l a c t i v i t y and r e s i d u a l properties of biphenyl-3-ylmethyl (1R,S)-cis-3-(2,2-dic h l o r o v i n y l ) - 2 , 2 - d i m e t h y l c y c l o p r o p a n e c a r b o x y l a t e were about o n e - h a l f t h a t o f the c o r r e s p o n d i n g 3-phenoxybenzyl e s t e r . The preparation of a s e r i e s of s u b s t i t u t e d d e r i v a t i v e s of biphenyl-3ylmethyl (1R,S)-cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylates resulted i n esters with s i g n i f i c a n t l y greater i n s e c t i c i d a l a c t i v i t y and b r o a d e r spectrum o f b i o l o g i c a l a c t i v i t y t h a n the c o n v e n t i o n a l p y r e t h r o i d i n s e c t i c i d e s ( 7 ) . The 2 - m o n o s u b s t i t u t e d d e r i v a t i v e s were found t o be the most a c t i v e compounds i n t h i s s e r i e s w i t h the 2-methyl compound b e i n g the most a c t i v e . T h i s r e s u l t encouraged us t o combine these b i p h e n y l - 3 - y l m e t h y l compounds w i t h a l k y l a r y l methanone oximes. The r e p l a c e m e n t o f the e s t e r l i n k a g e o f p y r e t h r o i d s by a l t e r n a t i v e s was known t o l e a d t o compounds o f d i m i n i s h e d b i o l o g i c a l activity. T h i o l e s t e r s and amides are two such i s o s t e r i c r e p l a c e ments t h a t l e a d t o a l o s s i n b i o l o g i c a l a c t i v i t y ( 1 3 . 1 4 ) . The e x c e p t i o n t o t h i s t r e n d was the r e p l a c e m e n t by the oxime f u n c t i o n ality(2,3). The a l k y l a r y l oxime e t h e r s are not s u s c e p t i b l e t o a l k a l i n e h y d r o l y s i s and e s t e r i c a t t a c k as are the p y r e t h r o i d e s t e r s ( 1 5 ) . The p r e s e n t s t u d y d e t a i l s our i n v e s t i g a t i o n o f the b i o l o g i c a l a c t i v i t y o f [1,1'-biphenyl]-3-methanols when combined w i t h a l k y l a r y l methanone oximes. The o b j e c t i v e s o f t h i s s t u d y were t o determine the e f f e c t on the b i o l o g i c a l a c t i v i t y by v a r y i n g the a l k y l p o r t i o n o f the oxime, c h a n g i n g the p a r a - s u b s t i t u e n t o f the a r y l group and v a r y i n g the E,Z r a t i o . The f o l i a r a c t i v i t y o f these compounds i s r e p o r t e d i n T a b l e II. T a b l e I I I r e p o r t s the s o i l i n s e c t i c i d a l a c t i v i t y o f the compounds o f i n t e r e s t . The f i r s t q u e s t i o n o f i n t e r e s t was t o compare 2-methyl[1,1'b i p h e n y l ] - 3 - m e t h a n o l w i t h 3-phenoxybenzyl a l c o h o l when combined w i t h the oximes o f c e r t a i n a l k y l a r y l k e t o n e s . The enhancement i n


16. CULLENETAL.


Table I.


A l k y l A r y l Oxime E t h e r s

Cmpd No.

Isomer

X

R

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

Ε Ε Ε Ε Ε Ε Ε,Ζ Ε Ε,Ζ Ε Ε Ε,Ζ Ε Ε,Ζ Ε Ε,Ζ Ε,Ζ Ε Ε,Ζ Ε Ε,Ζ Ε Ε,Ζ Ε Ε,Ζ Ε Ε Ε Ε Ε

4-C1 4-C1 4-C1 4-C1 4-F 4-F 4-Br 4-Br 4-Br 4-Br 4-CF 4-CF3 4-CF3 4-OCF3 4-OCF3 4-OCF3 4-OCF3 4-OCF3 4-OCF3 4-SCF3 4-SCF3 4-SC H 4-SC H 4-OC F H 4-OC F H 4-CH(CH ) 4-C H 4-C(CH ) 4-OCF H 4-1 3

2

5

2

5

2

4

2

4

2

5

3

3

2

3

2

isopropyl isopropyl cyclopropyl cyclopropyl cyclopropyl cyclopropyl isopropyl isopropyl cyclopropyl cyclopropyl cyclopropyl isopropyl isopropyl cyclopropyl cyclopropyl isopropyl ethyl ethyl methyl cyclopropyl cyclopropyl cyclopropyl cyclopropyl cyclopropyl cyclopropyl cyclopropyl cyclopropyl cyclopropyl cyclopropyl cyclopropyl

R

1

PB BPM PB BPM BPM PB BPM BPM BPM BPM BPM BPM BPM BPM BPM BPM BPM BPM BPM BPM BPM BPM BPM BPM BPM BPM BPM BPM BPM BPM

PB = 3-Phenoxybenzyl BPM = [ 1 , 1 ' - B i p h e n y l ] - 2 - m e t h y l - 3 - y l


179

180


Table I I .

F o l i a r A c t i v i t y o f A l k y l A r y l Oxime E t h e r s

Cmpd No.

MBB


LC

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

* D

c

d

a 5 0

35.0 13.9 100.0 2.4 10.1 I 55.0 14.0 6.0 5.3 15.4 40.0 15.0 22.9 5.3 45.0 7.3 6.0 I 4.5 17.5 6.0 3.0 3.2 11.4 3.5 2.4 4.1 0.9 38.1

SAW RP

0. 1 0. 1 0. 1 0. 6 0. 2 0. 1 0. 1 0. 2 0. 2 0.,1 0.,1 0..1 0..1 0..2 0,.1 0,.1 0,.8 0 .2 0 .1 0 .2 0 .4 0 .2 0 .1 0 .2 0 .3 0 .2 0 .8 0 .1

b

LÇ50

19. 0 14. 0 11. 2 1. 3 84. 0 I ND 42.,0 6.,0 5.,7 28.,7 10. 0 16,.8 4,.9 2,.2 50,.0 3 .4 6 .0 55 .0 4 .6 5 .7 24 .0 32 .0 0 .1 4 .5 I 71 .5 ND 1 .2 4 .8 d

TSM R£

0. 1 0. 1 0. 3 0. 9 0. 3 ND 0. 1 0. 2 0. 2 1. 2 0.,2 0,.1 0.,3 0..4 0..1 0,.5 0,.3 0,.1 0,.3 0 .2 0 .1 0 .1 4 .5 0 .3 0 .3 ND 0 .9 0 .3

LÇ50

e

I I I 10.3 I I I I I ND 5.3 50.0 ND 1.3 1.2 45.0 ND 4.0 I 2.7 3.7 48.0 ND 0.3 3.4 ND I 6.5 5.8 38.2

EE 0.6 ND 1.1 0.1 ND 4.4 4.4 0.1 ND 1.1 1.5 0.4 0.1 ND 3.4 0.4 ND 1.0 1.0 0.1

LC (ppm) RP - v s c y p e r m e t h r i n I - Inactive ND - No d a t a 5 0


1β.

CULLENETAL.

Table I I I .

S o i l A c t i v i t y o f A l k y l A r y l Oxime E t h e r s

Cmpd No.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

SCR LÇ50

a

I I I 0.6 I I I I I I 0.5 I I 0.4 0.5 I I 2.1 I 3.7 4.1 2.1 3.5 1.3 2.5 2.5 2.4 I 0.8 1.6

a

RP

0.5 0.6 0.7 0.6 0.2 0.2 0.1 0.3 0.2 0.3 0.1 0.2 0.2 0.4 0.3

R e s i d u a l A c t i v i t y (% c o n t r o l ) 7 day 14 day 28 day

80 100 100 100 30 40 25 64 75 100 50 65 75 90 35

I = I n a c t i v e a t 4 ppm - No f u r t h e r

50 10 70 40 25 40 15 15 5 35 85 40 25

30 10 90 40 5 65 0 -

testing


181



182

a c t i v i t y w i t h the b i p h e n y l a l c o h o l can be seen i n T a b l e IV. In b o t h c a s e s , the a r y l a l k y l oxime e t h e r s d e r i v e d from 2-methyl[1,1'b i p h e n y l ] - 3 - m e t h a n o l were c o n s i s t e n t l y more a c t i v e t h a n those d e r i v e d from 3-phenoxybenzyl a l c o h o l . Next, the e f f e c t on a c t i v i t y w i t h r e s p e c t t o the s i z e o f the a l k y l group i n our s e r i e s compared t o t h a t d i s c l o s e d i n the l i t e r a t u r e (2,4) was o f i n t e r e s t . The e f f e c t i v e n e s s o f a l k y l groups i s r e p o r t e d to be c y c l o p r o p y l > i s o p r o p y l > e t h y l > m e t h y l . I n f a c t , t h i s t r e n d was f o l l o w e d i n the [ 1 , 1 ' - b i p h e n y l ] - 2 - m e t h y l - 3 methanol d e r i v e d a l k y l a r y l oxime e t h e r s . This i s i l l u s t r a t e d with the (Ε,Z)-4-trifluoromethoxyphenyl(alkyl)methanone oxime e t h e r s , Compounds 14, 16, 19 ( T a b l e V ) . The a c t i v i t y o f t h i s s e r i e s i n c r e a s e s w i t h i n c r e a s i n g s i z e o f the a l k y l group. However, when c y c l o b u t y l was i n c o r p o r a t e d , a c t i v i t y was l o s t . The c y c l o p r o p y l was the most e f f e c t i v e w h i l e the i s o p r o p y l group was somewhat l e s s effective. O t h e r a l k y l changes r e s u l t e d i n a r a p i d l o s s o f activity. The a c t i v i t y o f the 3-phenoxybenzyl a l k y l a r y l oxime e t h e r s i s r e p o r t e d to r e s i d e i n the E-isomer. The a c t i v i t y o f the E-isomer was compared w i t h the a c t i v i t y o f the Ε,Ζ a l k y l a r y l oxime e t h e r s f o r t h i s new s e r i e s . T h i s t r e n d a l s o o c c u r s i n the biphenylmethylm e t h y l a l k y l a r y l oxime e t h e r s ( T a b l e V I ) . The d i s c o v e r y o f b i o l o g i c a l a c t i v i t y a g a i n s t the s o u t h e r n c o r n rootworm ( D i a b r o t i c a u n d e c i p u n c t a t a H o w a r d i i ) was an u n a n t i c i p a t e d r e s u l t from t h i s r e s e a r c h program. The t r e n d s i n b i o l o g i c a l a c t i v i t y o f the a l k y l a r y l methanone oxime e t h e r s d e r i v e d from 3 - c h l o r o m e t h y l - 2 - m e t h y l [ 1 , 1 ' - b i p h e n y l ] c l o s e l y p a r a l l e l e d the oxime e t h e r s d e r i v e d from 3-phenoxybenzyl c h l o r i d e . The major d i f f e r e n c e was the enhanced b i o l o g i c a l a c t i v i t y a g a i n s t a w i d e r v a r i e t y o f i n s e c t s by the b i p h e n y l m e t h y l d e r i v a t i v e s . When t h e s e compounds were t e s t e d i n a s o i l environment a g a i n s t the s o u t h e r n c o r n rootworm, the m e t h y l b i p h e n y l m e t h y l oxime e t h e r s were a c t i v e . None o f the 3-phenoxybenzyl oxime e t h e r s were a c t i v e a t the r a t e s t e s t e d a g a i n s t t h i s s o i l - b o r n e i n s e c t (Table I I I ) . QSAR. An a n a l y s i s o f the a c t i v i t y o f oxime e t h e r s was under t a k e n t o f u r t h e r our u n d e r s t a n d i n g o f the SAR i n t h i s system. A l l a n a l y s e s were p e r f o r m e d u t i l i z i n g a FMC p r o p r i e t a r y Q u a n t i t a t i v e S t r u c t u r e A c t i v i t y R e l a t i o n s h i p s (QSAR) s o f t w a r e system. Param e t e r s f o r s t r u c t u r e - a c t i v i t y s t u d i e s were o b t a i n e d as p r e v i o u s l y Table

IV.

Comparison o f BPM

v s PB A l k y l A r y l Oxime LC

Cmpd

1 2 3 4

No

R

isopropyl isopropyl cyclopropyl cyclopropyl

Ar

PB BPM PB BPM

5 0

Ethers

(ppm)

MBB

SAW

TSM

35.0 13.9 100 2.3

19.0 14.0 11.2 1.3

I I I 10.3



1β. CULLENETAL.


d e s c r i b e d ( 5 ) . A d e s c r i p t i o n o f the t e c h n i q u e s u s e d i n t h e s t r u c t u r e - a c t i v i t y s t u d i e s has been d e s c r i b e d ( 8 ) . Biological a c t i v i t y u s e d f o r QSAR a n a l y s i s was f o l i a r a c t i v i t y a g a i n s t s o u t h e r n c o r n rootworm e x p r e s s e d as L C 5 0 i n u n i t s o f ppm. The s e t o f compounds s t u d i e d r e p r e s e n t s s u b s t i t u t i o n i n t h e a r o m a t i c r i n g f o r t h e c y c l o p r o p y l compounds shown i n T a b l e V I I . I n t e r e s t i n g l y , o n l y t h e p a r a m o n o s u b s t i t u t e d compounds d i s p l a y e d a c t i v i t y , s u g g e s t i n g some s t r i c t a c t i v i t y r e q u i r e m e n t s , perhaps s t e r i c i n n a t u r e , a t t h e o r t h o and meta p o s i t i o n s . D i s c r i m i n a n t a n a l y s i s was p e r f o r m e d on a l l 22 compounds. Compounds were a s s i g n e d t o t h e " a c t i v e " s e t i f t h e a c t i v i t y was L C 5 0 - 5 ppm o r lower. A l l o t h e r s were d e s i g n a t e d " i n a c t i v e " . Stepwise d i s c r i m i n a n t a n a l y s i s BMDP-7M (16) was p e r f o r m e d u s i n g t h e f o l l o w i n g p h y s i c o c h e m i c a l d e s c r i p t o r s as v a r i a b l e s : p i , (17) Hammett σ, F, R, (18) and molar r e f r a c t i v i t y . The sum o v e r s u b s t i t u t e d p o s i t i o n s f o r each o f t h e s e parameters was u s e d f o r m u l t i p l y - s u b s t i t u t e d compounds. A s e t o f l i n e a r c l a s s i f i c a t i o n f u n c t i o n s i n t h e summation o f R was found t o be s t a t i s t i c a l l y s i g n i f i c a n t a t t h e 5% l e v e l , b u t the c l a s s i f i c a t i o n o f t h e s e 22 compounds was o n l y 73 p e r c e n t c o r r e c t , m i s s i n g 3 o f t h e a c t i v e s e t . active f ( Z R ) = -2.53 ER - 0.76 inactive f ( E R ) — -10.4 ER - 1.93 l,20( PP - ) = 7.75 ( Σσ > -0.2 and Σπ > 0.3. F u r t h e r , t h e f i v e most a c t i v e compounds f e l l i n t h e range 0.5 > ΣΥ > 0.3, and a l l o f t h e a c t i v e compounds were i n t h e range d e f i n e d by ZF < 0.5 and ER > -0.3. E l e c t r o n i c c h a r a c t e r appeared t o be one o f t h e i m p o r t a n t f a c t o r s r e l a t i n g t o b i o l o g i c a l activity. Using d i s c r i m i n a n t a n a l y s i s , the f o l l o w i n g non-linear c l a s s i f i c a t i o n f u n c t i o n s were g e n e r a t e d i n Σσ space a l s o a l l o w i n g d i s c r i m i n a t i o n between a c t i v e and i n a c t i v e s e t s . However, t h e p a r a b o l i c f u n c t i o n s i n Σσ were no more s t a t i s t i c a l l y s i g n i f i c a n t t h a n t h e f u n c t i o n s i n ΣΚ and c l a s s i f i c a t i o n was s t i l l o n l y 73 p e r c e n t c o r r e c t , m i s s i n g two o f t h e a c t i v e s e t . (19) 2

active £(Σσ) - 2.51 Σσ -2.09 Σσ i n a c t i v e ί(Σσ) - -4.98 Σα + 10.81 Σ α F i 9 ( a p p r o x . ) - 5.40 ( 8

(0.0038)

E x c l u s i o n o f the 4-SCF3 compound from the r e g r e s s i o n r e v e a l e d more s t a t i s t i c a l l y s i g n i f i c a n t e q u a t i o n i n σ.

a

l o g ( l / L C ) - 1.11 (0.23) σ - 0.23 η = 9, s - 0.14, r - 0.88, F - 23.94 (0.0018) 5 0

1

7

A l t h o u g h i t might be i m a g i n e d t h a t the -SCF3 group c o u l d e a s i l y be o x i d i z e d , t h i s does n o t a d e q u a t e l y d i s t i n g u i s h t h i s group from, f o r example, the -SCH3 compound and t h e r e f o r e cannot, a l o n e , form a r a t i o n a l e f o r e x c l u s i o n o f o n l y the -SCF3 compound. It is inter e s t i n g t o n o t e t h a t one p r o p e r t y w h i c h might d i s t i n g u i s h the -SCF3 f u n c t i o n a l i t y i s the p o t e n t i a l f o r homologous c l e a v a g e f o r the bond between the s u l f u r and t r i f l u o r o m e t h y l i n t h i s group. S t e p w i s e m u l t i p l e r e g r e s s i o n (BMDP-2R) o f t h i s s e t o f n i n e compounds ( e x c l u d i n g the -SCF3 compound) y i e l d e d the e q u a t i o n i n σ and m o l a r r e f r a c t i v i t y shown below: ) - 0.734 (0.219) σ + 0.138 η - 9, r - 0.95, s - 0.10,

log(l/LC

5 0

- 0.029 (0.011) F

s 2

6

2 6

-°

MR

(

Insecticidal Substituted Biphenylmethyl Oxime Ethers - ACS Publications

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